Reduction in hepatic drug metabolizing CYP3A4 activities caused by P450 oxidoreductase mutations identified in patients with disordered steroid metabolism

被引:44
作者
Flueck, Christa E. [1 ]
Mullis, Primus E. [1 ]
Pandey, Amit V. [1 ]
机构
[1] Univ Bern, Dept Clin Res, CH-3004 Bern, Switzerland
基金
瑞士国家科学基金会;
关键词
CYP3A4; NADPH P450 oxidoreductase; POR; CPR; Steroid metabolism; Antely-Bixler syndrome; Adrenal hyperplasia; Drug metabolism; ANTLEY-BIXLER-SYNDROME; CONGENITAL ADRENAL-HYPERPLASIA; CYTOCHROME-P450; OXIDOREDUCTASE; HUMAN-LIVER; NADPH-CYTOCHROME-P-450; REDUCTASE; NADPH-P450; DEFICIENCY; STEROIDOGENESIS; INHIBITION; 3A4;
D O I
10.1016/j.bbrc.2010.09.035
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Cytochrome P450 3A4 (CYP3A4), the major P450 present in human liver metabolizes approximately half the drugs in clinical use and requires electrons supplied from NADPH through NADPH-P450 reductase (POR, CPR). Mutations in human POR cause a rare form of congenital adrenal hyperplasia from diminished activities of steroid metabolizing P450s. In this study we examined the effect of mutations in POR on CYP3A4 activity. We used purified preparations of wild type and mutant human POR and in vitro reconstitution with purified CYP3A4 to perform kinetic studies. We are reporting that mutations in POR identified in patients with disordered steroidogenesis/Antley-Bixler syndrome (ABS) may reduce CYP3A4 activity, potentially affecting drug metabolism in individuals carrying mutant POR alleles. POR mutants Y181D, A457H, Y459H, V492E and R616X had more than 99% loss of CYP3A4 activity, while POR mutations A287P, C569Y and V608F lost 60-85% activity. Loss of CYP3A4 activity may result in increased risk of drug toxicities and adverse drug reactions in patients with POR mutations. (C) 2010 Elsevier Inc. All rights reserved.
引用
收藏
页码:149 / 153
页数:5
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